CDK7 Inhibition Synergizes with Topoisomerase I Inhibition in Small Cell Lung Cancer Cells by Inducing Ubiquitin-Mediated Proteolysis of RNA Polymerase II

Small cell lung cancers (SCLC) are highly aggressive, and currently there are no available targeted therapies. To identify clinically actionable drug combinations, we analyzed our previously reported chemogenomics screens and identified a synergistically cytotoxic combination of the topoisomerase I (TOP1) inhibitor topotecan and cycle-dependent kinase 7 (CDK7) inhibitor THZ1. Topotecan causes cell death by generating TOP1-induced DNA breaks and DNA-protein cross-links (TOP1-DPC) that require proteolysis by the ubiquitin-proteasome pathway for their repair. We find that inhibition of the transcriptional kinase CDK7 by THZ1 induces ubiquitin-mediated proteasomal degradation of RNA polymerase II and prevents the proteasomal degradation of TOP1-DPCs. We provide a mechanistic basis for combinatorial targeting of transcription using selective inhibitors of CDK7 and TOP1 in clinical trials to advance SCLC therapeutics.